Personality Disorders as a Basis for Discharge and Denial of Benefits in the Military: Logical or Abusive?

ABSTRACT: The US Department of Defense specifically states that intellectual disability and personality disorders are not diseases for compensation purposes, and disabilities from them may not be service connected absent a superimposed mental disorder. In addition, the diagnosis of a personality disorder led to the discharge of 31,000 troops during the years 2001 to 2010. I review the history of these developments, and how the Diagnostic and Statistical Manual of Mental Disorders enabled these actions. In contrast, the United Kingdom and Canada do not allow such actions. Whether our approach is logical seems highly questionable, especially given the significant problems with the DSM's definitions of personality disorders, definitions at odds with the literature.

Whither Research Domain Criteria?

In 2010, the National Institute of Mental Health launched the Research Diagnostic Criteria (RDoC) as a research framework aimed at advancing research into the etiology of mental disorders, the development of clinically actionable biomarkers, and the eventual development of precision medications. The foundation of RDoC in that first phase rested in the assumption that mental disorders are brain disorders that originate in aberrant neural circuitry, and that therapeutic advances could flow from alterations in that circuitry. RDoC proposed a matrix of psychological constructs with seven levels of analysis ranging from the cell to self-report, but with neural circuitry at the center. In 2016, another model was proposed in which neural circuitry became equivalent to other units of analyses. With the advent of a new Director of the NIMH, the emphasis returned to neural circuitry as a priority, along with computational psychiatry. Have these shifts undermined the RDoC project?

The nature of bradykinesia in schizophrenia treated with antipsychotics.

Recognizing drug-induced parkinsonian bradykinesia in psychosis patients can be challenging due to overlapping presentation with psychomotor slowing associated with depression, negative symptoms, or cognitive disturbances. In this study, we apply prior findings on the pathophysiology of bradykinesia in Parkinson's disease to gain an understanding of motor slowing in psychosis patients. Handwriting movements from 57 healthy participants and 70 psychosis patients were recorded on a digitizing tablet. Temporal and kinematic features were extracted from handwritten loops and circles. An independent objective measure based on peak velocity for circles written at maximum speed was used to classify patients as bradykinetic. Using a statistical cut-point derived from normative data, 64% of the patients met criterion for bradykinesia compared with 46% using a conventional observer-based severity rating scale. Bradykinetic patients produced handwriting movements with longer stroke durations, smaller amplitudes and lower peak velocities compared with non-bradykinetic patients. Thirty-six percent of the pen strokes produced by the bradykinetic patients were non-ballistic compare with 20% for the non-bradykinetic patients. The proportion of nonballistic movements observed in handwriting was unrelated to current antipsychotic dose, severity of negative psychosis or depression. The ease-of-use and standardization of a tablet-based approach to quantifying parkinsonian bradykinesia can aid in diagnosing parkinsonian bradykinesia in patients treated with antipsychotics.

Neural circuitry and precision medicines for mental disorders: are they compatible?

Given the failure of psychiatry to develop clinically useful biomarkers for psychiatric disorders, and the concomitant failure to develop significant advances in diagnosis and treatment, the National Institute of Mental Health (NIMH) in 2010 launched the Research Domain Criteria (RDoC), a framework for research based on the assumption that mental disorders are disorders of identifiable brain neural circuits, with neural circuitry at the center of units of analysis ranging from genes, molecules, and cells to behavior, self-reports, and paradigms. These were to be integrated with five validated dimensional psychological constructs such as negative and positive valence systems. Four years later, the NIMH stated that the ultimate goal of RDoC is precision medicine for psychiatry, with the assumption that precision medications will normalize dysfunctional neural circuits. How this could be accomplished is not obvious, given that neural circuits are widely distributed, have unclear boundaries, and exhibit a significant degree of neuroplasticity, with multiple circuits present in any given disorder. Moreover, the early focus on neural circuitry has been criticized for its reductionism and neglect of the more recent RDoC emphasis on the integration and equivalence of biological and psychological phenomena. Yet this seems inconsistent with the priorities of the NIMH director, an advocate of the central role of neural circuitry and projects such as the Brain Initiative and the Human Connectome Project. Will such projects, at a cost of at least $10 billion, lead to precision medications for mental disorders, or further diminish funding for clinical care and research?

Social inequality, scientific inequality, and the future of mental illness.

BACKGROUND: Despite five decades of increasingly elegant studies aimed at advancing the pathophysiology and treatment of mental illness, the results have not met expectations. Diagnoses are still based on observation, the clinical history, and an outmoded diagnostic system that stresses the historic goal of disease specificity. Psychotropic drugs are still based on molecular targets developed decades ago, with no increase in efficacy. Numerous biomarkers have been proposed, but none have the requisite degree of sensitivity and specificity, and therefore have no usefulness in the clinic. The obvious lack of progress in psychiatry needs exploration. METHODS: The historical goals of psychiatry are reviewed, including parity with medicine, a focus on diagnostic reliability rather than validity, and an emphasis on reductionism at the expense of socioeconomic issues. Data are used from Thomas Picketty and others to argue that our failure to advance clinical care may rest in part on the rise in social and economic inequality that began in the 1970s, and in part on our inability to move beyond the medical model of specificity of disease and treatment. RESULTS: It is demonstrated herein that the historical goal of specificity of disease and treatment has not only impeded the advance of diagnosis and treatment of mental illness, but, in combination with a rapid increase in socioeconomic inequality, has led to poorer outcomes and rising mortality rates in a number of disorders, including schizophrenia, anxiety, and depression. CONCLUSIONS: It is proposed that Psychiatry should recognize the fact of socioeconomic inequality and its effects on mental disorders. The medical model, with its emphasis on diagnostic and treatment specificity, may not be appropriate for investigation of the brain, given its complexity. The rise of scientific inequality, with billions allocated to connectomics and genetics, may shift attention away from the need for improvements in clinical care. Unfortunately, the future prospects of those suffering from mental illness appear dim.

A quantitative measure of handwriting dysfluency for assessing tardive dyskinesia.

Tardive dyskinesia (TD) is a movement disorder commonly associated with chronic exposure to antidopaminergic medications, which may be in some cases disfiguring and socially disabling. The consensus from a growing body of research on the incidence and prevalence of TD in the modern era of antipsychotics indicates that this disorder has not disappeared continues to challenge the effective management of psychotic symptoms in patients with schizophrenia. A fundamental component in an effective strategy for managing TD is its reliable and accurate assessment. In the present study, we examined the clinical utility of a brief handwriting dysfluency measure for quantifying TD. Digitized samples of handwritten circles and loops were obtained from 62 psychosis patients with or without TD and from 50 healthy subjects. Two measures of dysfluent pen movements were extracted from each vertical pen stroke, including normalized jerk and the number of acceleration peaks. Tardive dyskinesia patients exhibited significantly higher dysfluency scores than non-TD patients and controls. Severity of handwriting movement dysfluency was correlated with Abnormal Involuntary Movement Scale severity ratings for some tasks. The procedure yielded high degrees of test-retest reliability. These results suggest that measures of handwriting movement dysfluency may be particularly useful for objectively evaluating the efficacy of pharmacotherapeutic strategies for treating TD.

The death of specificity in psychiatry: cheers or tears?

During the past five decades, psychiatry has pursued two goals, one being specificity of diagnosis and treatment, and the other a series of all-inclusive diagnostic manuals that paradoxically emphasized the absence of definite boundaries between disorders, and the absence of definite boundaries between disorders and normality (although normality was never defined). Leaders in the field continue to emphasize that diagnoses must be validated by the pathogenesis, course, and response to treatment of specific disorders. However, many current genetic and family studies have failed to support the concept of diagnostic specificity, as has the current use of psychotropic agents, which are now being prescribed with little regard for diagnosis. Although the switch from a categorical diagnostic system to a dimensional system has not been formalized, it seems to have already occurred in practice.

Psychopharmacology: a house divided.

BACKGROUND: Psychopharmacology and psychiatry during the past 50 years have focused on the specificity model in which it is assumed that psychiatric disorders are specific entities which should respond to drugs with specific mechanisms of action. However, the validity of this model has been challenged by the approval of multiple drugs for the same disorder, as well as the approval of single agents for a variety of disorders which have little in common. As an example of this unacknowledged paradigm shift, I will examine the foundation for using antipsychotics in the treatment of depression. METHODS: An extensive literature search of studies investigating various mechanisms of actions of antipsychotics and antidepressants with the goal of identifying neurochemical processes common to both. RESULTS: The neurochemical differences in these classes of drugs appear to be profound, although several processes are common in both, including some degree of neuroprotection and changes in the epigenome. Whether these common features have any effect on clinical outcome remains in doubt. CONCLUSIONS: While psychopharmacology and psychiatry remain largely committed to the specificity model, it appears that clinicians are prescribing on a dimensional model wherein symptoms are being treated with a variety of drugs, regardless of the diagnosis.

Handwriting movement kinematics for quantifying extrapyramidal side effects in patients treated with atypical antipsychotics.

Ongoing monitoring of neuroleptic-induced extrapyramidal side effects (EPS) is important to maximize treatment outcome, improve medication adherence and reduce re-hospitalization. Traditional approaches for assessing EPS such as Parkinsonism, tardive akathisia, or dyskinesia rely upon clinical ratings. However, these observer-based EPS severity ratings can be unreliable and are subject to examiner bias. In contrast, quantitative instrumental methods are less subject to bias. Most instrumental methods have only limited clinical utility because of their complexity and costs. This paper describes an easy-to-use instrumental approach based on handwriting movements for quantifying EPS. Here, we present findings from psychiatric patients treated with atypical (second generation) antipsychotics. The handwriting task consisted of a sentence written several times within a 2 cm vertical boundary at a comfortable speed using an inkless pen and digitizing tablet. Kinematic variables including movement duration, peak vertical velocity and the number of acceleration peaks, and average normalized jerk (a measure of smoothness) for each up or down stroke and their submovements were analyzed. Results from 59 psychosis patients and 46 healthy comparison subjects revealed significant slowing and dysfluency in patients compared to controls. We observed differences across medications and daily dose. These findings support the ecological validity of handwriting movement analysis as an objective behavioral biomarker for quantifying the effects of antipsychotic medication and dose on the motor system.

Handwriting movement analyses for monitoring drug-induced motor side effects in schizophrenia patients treated with risperidone.

Epidemiologic studies indicate that nearly 60% of schizophrenia (SZ) patients treated with conventional antipsychotic drugs develop extrapyramidal side effects (EPS) such as parkinsonism and tardive dyskinesia. Although the prevalence of EPS has decreased due to the newer antipsychotics, EPS continue to limit the effectiveness of these medicines. Ongoing monitoring of EPS is likely to improve treatment outcome or compliance and reduce the frequency of re-hospitalization. A quantitative analysis of handwriting kinematics was used to evaluate effects of antipsychotic medication type and dose in schizophrenia patients. Twenty-seven schizophrenia patients treated with risperidone, six schizophrenia patients who received no antipsychotic medication and 47 healthy comparison participants were enrolled. Participants performed a 20-min handwriting task consisting of loops of various sizes and a sentence. Data were captured and analyzed using MovAlyzeR software. Results indicated that risperidone-treated participants exhibited significantly more dysfluent handwriting movements than either healthy or untreated SZ participants. Risperidone-treated participants exhibited lower movement velocities during production of simple loops compared to unmedicated patients. Handwriting dysfluency during sentence writing increased with dose. A 3-factor model consisting of kinematic variables derived from sentence writing accounted for 83% (r=.91) of the variability in medication dose. In contrast, we found no association between observer-based EPS severity ratings and medication dose. These findings support the importance of handwriting-based measures to monitor EPS in medicated schizophrenia patients.

Personalized medicine: boon or budget-buster?

While the development of personalized or molecular medicine is a laudable goal, there remain multiple barriers to its implementation. For example, little is known about the functions of noncoding regions of DNA, as well as the interplay of drug response, environmental factors, and the patient's genetic profile. In addition, there is a constant influx of new information on genetic factors such as epigenetic variation that could further complicate the development of medications based on the genetic profile, as well as the cost of profiling. However, assuming that clinically relevant genetic factors will be discovered and that drugs can be developed based on the molecular changes induced by those genetic factors, I suggest that the costs involved may substantially exceed the savings brought about by abandoning our current "one drug fits all" approach. While there is no doubt that our current approach is inefficient and expensive, remarkably little attention has been paid to the potential costs of molecular medicine. Given the current economic crisis, the time is ripe for a debate on this issue.

Mortality and tardive dyskinesia: long-term study using the US National Death Index.

BACKGROUND: Whether the development of tardive dyskinesia leads to an increase in mortality is still unclear. AIMS: To explore the relationship between tardive dyskinesia and mortality over a 10-year period, using the National Death Index. METHOD: Death certificates were obtained from the National Death Index on 1621 people repeatedly assessed for tardive dyskinesia by trained raters. Variables with the potential for influencing survival time were also investigated. RESULTS: Tardive dyskinesia was significantly associated with an increase in mortality (P<0.001), but this association became non-significant when drug course and age were entered in the regression analysis. Those who had taken only conventional antipsychotics were twice as likely to die compared with those taking atypical agents (P<0.02). For those aged 53-65 years, conventional agents were associated with a sevenfold increase in mortality. CONCLUSIONS: Older individuals with tardive dyskinesia treated with conventional antipsychotics appear to have a shortened survival time.

Predictors of neuroleptic-induced dyskinesia and parkinsonism: the influence of measurement methods and definitions.

The accurate and objective measurement of abnormal, involuntary movements remains highly desirable, whether the movements are secondary to pharmacotherapy or an expression of the primary illness. In a previous study, we found that the prevalence of tardive dyskinesia in a sample of 100 subjects ranged from 28% when using the Abnormal Involuntary Movement Scale (AIMS) or the Dyskinesia Identification Scale, Condensed User Version (DISCUS) to 62% using an instrumental measurement (IM) of peripheral dyskinesia. The goal of this study was to examine the relationship between various risk factors for tardive dyskinesia as predictor variables, and the AIMS, DISCUS, and IMs of dyskinesia, tremor, and velocity of motor movement as dependent variables. The sample consisted of 100, mostly patients with schizophrenia. Poor performance on the Mini-Mental State Examination (MMSE) and increasing age were the most consistent predictors of dyskinetic and parkinsonian movements. Various predictors were associated with specific abnormal movements. Head injury was related to slower speed of motor movements and the total DISCUS score. A history of smoking was associated with less IM dyskinesia. For those with coexisting parkinsonism and dyskinesia, significant associations were found with head injury, diabetes mellitus, and an AIMS score of 2 or greater in 2 body areas. Various classes of psychotropic agents seemed to have little influence on the MMSE or the development of dyskinesia and parkinsonism. Increasing age and a lower score on the MMSE seem to be particularly helpful in gauging the risk for parkinsonian and dyskinetic movements.

Antipsychotic-associated neuronal changes in the brain: toxic, therapeutic, or irrelevant to the long-term outcome of schizophrenia?

The increasingly wide-spread use of antipsychotics in both adults and children calls for a detailed examination of antipsychotic-associated neuronal changes in the brain, and whether these changes are toxic, therapeutic, or perhaps irrelevant to the outcome of major psychiatric disorders, especially schizophrenia. In this review we will examine the extensive evidence demonstrating both acute and longer-term antipsychotic-associated neurotoxicity and neuroplasticity, as well as the more specific cellular changes that appear to underlie these phenomena. These include changes in proteins affecting cell survival, impairment of the mitochondrial respiratory chain, increases in DNA fragmentation, injury to dendritic microtubules, increases in dopamine-generated reactive oxygen species, changes in cell morphology, and rapid induction of apoptosis. We shall also examine the correlation between these changes and alterations in gross brain structure. There appears to be a disjunction between the widespread cellular and gross structural brain changes in schizophrenia, and the duration of illness, expression of symptoms, and response to treatment. We shall explore possible explanations for this apparent paradox.

Ziprasidone-associated mania: a review and report of 2 additional cases.

Although mania was not reported as an adverse event in the pivotal trials of ziprasidone, there have been 7 reports of ziprasidone-induced mania in 12 patients. We now report 2 additional cases wherein the introduction of ziprasidone resulted in new-onset manic episodes. In 1 case, the patient required hospitalization and lost his job. In the other, time to mania was 5 months, considerably longer than previously reported. Of the 14 cases, 9 were in a depressive episode when ziprasidone was prescribed, and 8 had a history of current or past exposure to antidepressants. Ziprasidone, like many antidepressants, can block reuptake of norepinephrine and serotonin, although mania has developed in patients treated with atypical antipsychotics that are less potent in this regard. However, ziprasidone and other atypical antipsychotics have in common a high ratio of 5-HT2a to D2 receptor blockade, which may also play a role in this phenomenon. Clinicians and patients need to be aware of the potential for the induction of mania with ziprasidone, even after lengthy exposure.

Regional induction of CYP1A1 in rat liver following treatment with mixtures of PCB 126 and PCB 153.

Liver enzyme induction has been shown previously to be regional with clear borders between induced and uninduced regions in vivo, and cells either fully induced or not induced in vitro. The current study examined this phenomenon in vivo by evaluating enzyme induction after exposure to PCB 126 and PCB 153 in female Fisher 344 (F344) and male Sprague-Dawley (SD) rats. IHC revealed a regional induction of CYP1A1 after exposure to PCB 126, apparent in the centrilobular region at lower doses and progressing to panlobular with higher doses. PCB 153 exposure induced CYP2B1/2 in the centrilobular region, which spread to the midzonal region as the dose increased, but never became panlobular even at the highest dosage tested. In rats treated with PCB 126 in combination with high doses of PCB 153, induction of CYP1A1 occurred preferentially in the periportal region, a reversal from the pattern seen with PCB 126 alone. This CYP1A1 induction pattern reversal is a unique example of complex biological interactions between coplanar (PCB 126) and noncoplanar (PCB 153) halogenated aromatic hydrocarbons.

Clinical rating scales and instruments: how do they compare in assessing abnormal, involuntary movements?

OBJECTIVE: Recent studies have shown that quantitative instrumental measurements are more sensitive than clinical rating scales to subclinical dyskinesia and parkinsonism. We therefore hypothesized that an instrumental assessment would be more sensitive to the presence of dyskinetic and parkinsonian movements than the Abnormal Involuntary Movement Scale (AIMS), the Dyskinesia Identification Scale, Condensed User Version (DISCUS), and the Simpson-Angus Scale (SAS). We also hypothesized that the DISCUS, by virtue of its more detailed protocol, would be more sensitive than the AIMS. METHOD: Using blinded raters, we compared the clinical rating scales with instrumental measurements in 100 patients referred to a movement disorders clinic. We collected demographic data, risk factors for tardive dyskinesia, current medication use, Axis I and III disorders, and an estimate of cognitive functioning using the Mini-Mental Status Examination. RESULTS: There was no significant difference between the AIM and the DISCUS in the identification of dyskinesia. However, an instrumental assessment revealed a significantly greater prevalence of dyskinesia. The Mini-Mental Status Examination was the most prominent predictor of both instrumental and clinical measurements of parkinsonian and dyskinetic movements. CONCLUSIONS: It appears that even trained raters, utilizing standard rating scales, may underestimate the prevalence of some motor abnormalities. Instrumental ratings may be helpful to both the clinician and investigator, particularly when abnormal movements are not clinically obvious. The relationship between cognitive impairment and motor abnormalities remains an important area for further research.